Compounds of the cyclopentanopolyhydrophenanthrene series and process of making same



Patented Oct. 23, 1945 COMPOUNDS OF THE CYCLOPENTANO-POLYHYDROPHENANTHRENE SERIES AND PROCESS OF MAKING SAME TadcusRelchstein, Basel, Switzerland No Drawing. Application January 12, 1943,Serial No. 472,158. In Switzerland April 15,1942

7 Claims. (Cl. 260-3971) In patent application Serial No. 433,072, filedMarch 2, 1942, a process is described for the manufacture of compoundsof the cyclopentanopolyhydrophenanthrene series which are substituted inring A and unsaturated in ring C. The compounds of the androstane andpregnane series which are used as starting products in this process canbe obtained, for example, by degrading the side chain of thecorresponding compounds of the cholanic acid series, which aresubstituted in the 12-position by a free or esterifled hydroxyl group,or their lower homologues.

It has now been found that similar compounds of thecyclopentanopolyhydrophenanthrene series with an unsaturated ring C, asin the above patent, can be obtained by degradation of the side chain ofcompounds of the cholanic acid series, which are substituted in ring Aand unsaturated in ring C, their lower homologues or theirstereoisomers, by an already known method.

Particularly suitable starting product are compounds of the cholanicacid series unsaturated in ring C, such as are obtained, as described inthe above patent, from corresponding compounds which have a free oresterified hydroxyl group in the 12-position and also, for example, afurther free or substituted hydroxyl or carbonyl group in the 3 and/or 7position. Besides the double bond in ring they may be saturated orunsaturated in the nucleus, completely or partly esterifled and, inaddition, of any steric configuration. The following compounds can, forexample, be used: A =-3;hydroxy-cholenic acid, A -ii-keto-choienic acid,A ='-3:'7-dihydroxy-cholenic acid, A -ii-hydroxy-choladienic acid, A=="-3- keto-choladienic acid, [F fi -3:7 di hydroxycholadienic acid, A3:I-diketo-choladienic acid, the corresponding derivatives esterified inthe hydroxyl and/or acid groups, and analogous compounds unsaturated inthe 9:1l-position or another position in ring C. The lower homologues ofthe above acids, such as are obtained, for example, from the aboveprocess by only partial degradation of the side chain, can also be used.

The side chain is degraded directly or in stages by a method alreadyknown per se. If carried out in stages, the so-called Wielands processcan very satisfactorily be used, 1. e. the acids or esters used asstarting products are converted by means of an organic-metallic compoundinto the corresponding tertiary carbinols, which are then oxidized, ifdesired after transforming them into the ethylene compounds. In this waythe next lowest homologous acids, or the pregnane or androstanecompounds, are obtained. This treatment is repeated with the acids whichmay be obtained until the pregnane or androstane compounds (17- ketonesor l'l-carboxylic acids) are formed. The pregnane compounds may also besubsequently converted, it required, into the corresponding androstanecompounds, by an already known method.

The initial acid compounds can also be subjected to, other known gradualdegradation. methods, for example, the Curtius or Hofmanns degradation.Otherwise the degradation can be eifected by radical oxidation, forexample by means of a hexavalent chromium compound, a permanganate, aperoxide or one of the other oxidizing agents, known for this reaction.In this case the acid and neutral degradation products of the androstaneseries are obtained in addition to the compounds of the pregnane seriesin one operation. Finally the degradation processes may be combined.

Sensitive substituents such as hydroxyl groups, keto groups or doublebonds are if necessary temporarily protected in a known manner duringthe various degradation reactions, the first preferably by acylation,the last by addition of halogen or hydrogen halide.

The products of the process under consideration are therapeuticallyvaluable substances or may be converted into such.

The following examples illustrate the invention, but are not to beregarded as limiting it in any way:

Example 1 A =-3-acetoxycholenic acid methyl ester, M. Pt. 117-118 C.(obtained according to patent application Serial No. 433,072) isconverted into 11:12-dibrom-3acetoxy-cholenic acid-methylester bydropping in a solution of bromine in acetic acid. 1 g. of the dibromcompound is dissolved in 30 c. c. glacial acetic acid (stable to chromicacid) and a solution of 1 g. chromium trioxide in 1 c. c. of water and 3c. c. of glacial acetic acid added at C. over a period of 30 minutes,stirring continually. Stirring is continued for 4 hours and thetemperature kept at about 70 (2. The green solution is evaporated downto a syrup in vacuo at 30-40 C., the residue dissolved in water and thesolution thoroughly extracted three times with ether. The ethersolutions are washed several times with 10 per cent. sulphuric acid,saturated aqueous bicarbonate solution, and water. After evaporatingdown the ether solution, the residue is dissolved in per cent. aceticacid and the bromine eliminated by vigorously stirring the solution withzinc dust for 10 hours at room temperature. The acetic acid solution isfiltered off by suction, diluted with much water and extracted withether. The ether solution is then washed with water, extracted withaqueous soda solution, dried and evaporated.

Some pure starting product is regenerated from this neutral fraction byre-crystallizing from methyl alcohol. The mother liquors are boiledunder reflux with 3 c. c. of 10 per cent. potassium hydroxide in methylalcohol for 2 hours. Subsequent separation gives a neutral fractionwhich yields a ketone fraction by separation with the chloride oftrimethyl-ammonium acetic acid hydrazide. The latter fraction isseparated chromatographically, using standardized aluminium oxide. Inthis way the a -ii-hydroxy-androstene-l'l-one and the A="-3-hydro:w-pregnene- 20-one are obtained. These two compounds have thefollowing constitutional formulas:

CH: g Hi0 00cm Hi0 J -QJ The acid degradation products are isolated byacidifying the soda solutions and extracting with the ether. The etherresidue is boiled for 2 hours with a 50 per cent. aqueous solution ofpotassium hydroxide. The mixture is then acidified, thoroughly extractedthree times with ether, the ether solution washed with water, dried, anda diazomethane solution added until a permanent yellow colouration isobtained. After minutes the majority of the ether is evaporated, theremainingsolution washed with dilute hydrochloric acid, soda solutionand water, dried and evaporated down. The methyl-ester mixture thusobtained is partially saponified by boiling for minutes with a 5 percent. solution of potassium needles melting at 99-100 C. and has aspecific rotation (in acetone) By dehydration of the A=-3-hydroxy-etiocholenic-acid-methyl-ester, with aluminium isopropylatein the presence of cyclohexanone, A-3-keto-etiochlolenic-acid-methylester, empirical formula CnHaoOu(described in patent application Serial No. 433,072) is obtained.

It melts in the pure state at 136-138 C. and has Example 2 See formulason pages 3 to 5.

(a) The solution of 6.3 g. A ="-3-hydroxycholenic-acid-methyl-ester,meltin at 102 0. (Formula I, obtained by partial saponification of A"-3-acetoxy-cholenic-acid-methyl-ester, M. Pt. l1'7-118 C., which is usedin Example 1 as starting product, by means of a 1 per cent. solutionhydroxide in methyl alcohol. After cooling, wa-

ter is added, the methyl alcohol distilled oil in vacuo at C. and theresidue twice extracted with ether. The ether solution is again washedwith some caustic soda solution and water, dried and evaporated down.The fraction of the dimcultly saponifiable ester thus obtained is boiledunder reflux with 10 per cent. potassium hydroxide in methyl alcohol for20 hours, diluted with water, the methyl alcohol evaporated, the residueextracted three times with ether and the ether solution washed severaltimes with water and a little caustic soda solution. The alkalineportions are acidified and extracted with ether and the ether residueesterified with diazomethane. In this way A-3-hydroxy-etiochlolenic-acidmethyl-ester is obtained with the followingformula:

CHI

This compound melts at 124-126 C. and has a specific rotation of (inacetone). The acetate of this compound forms, on recrystallization frompetroleum ether,

of hydrogen chloride in methyl alcohol) in 30 c. c. of benzene isallowed to run into a Grignard solution prepared from 6 g. magnesiumfilings, 22 c. c. brom-benzene and 60 c. c. of ether. The ether isdistilled off and the mixture heated under reflux on a water-bath for 4hours. After decomposition with ice and ammonium chloride, the mixtureis extracted with ether, the other solution washed with dilutehydrochloric acid, soda and water, dried over sodium sulphate andevaporated down. To remove the unchanged ester the residue is boiled for30 minutes, under reflux, with a solution of 0.8 g. potassium hydroxidein 2 c. c. of water and 20 c. c. of alcohol. On working up as neutralproduct there is obtained A 3-hydroxy-nor-cholenyl-diphenyl-carbinol(Formula II) in crude form. V

(b) The product mentioned is dissolved in 20 c. c. of pyridine, 1'7 0.c. of acetic anhydride added and the whole allowed to stand for 16 hoursat room temperature. After evaporating down in vacuo, the residue isdissolved in ether, washed with dilute hydrochloric acid, soda solutionand water, dried over sodium sulphate and evaporated down. The residuecrystallizes out after standing for three days, from a little ether. Theseparation of crystals is completed as far as possible by the cautiousaddition of petroleum ether. Crystals of the mono-acetate, Formula III,M. Pt. 152-154- C., are obtained. For analysis the substance is againrecrystallized from ether and petroleum ether. Colorless platelets,melting at 153-155 C., are obtained. Specific rotation (c=0.887 inacetone).

(0) 3.55 g. of the crystalline carbinol, Formula III, are boiled underreflux for 2 hours with 15 c. c. of glacial aceticacid. On working upcrystals of the acetyiated ethylene, Formula IV, M. Pt. 142-144 C., areobtained. For analysis the substance is again recrystallized frompetroleum ether, when platelets melting at 144-145 C. are obtained.

(11) 2.4 g. of the acetylated ethylene (Formula IV) M. Pt. 142-144 C.are dissolved in 15 c. c. of glacialacetic acid (stable to chromic acid)and 5 c. c. of chloroform. The solution of 1.5 g. of chromium trioxldein 1 c. 0. water and 7.5 c. c. glacial acetic acid is added, coolinggently, and the whole kept at a temperature of exactly 25 C. (internaltemperature) for 2 hours. The mixture is then evaporated down in vacuo,water added to the residue, the whole thoroughly extracted with etherand the ether solution washed several times with water. The mixture isthen separated as usual with 2n soda solution, in the presence of ice,into neutral and acid components. The acid mostly separates oil as thesparingly soluble sodium salt, whereas the unchanged ethylene compoundcan be regenerated from the neu-' tral portion in the crystalline form.

The crude acid gives, from ether, crystals which melt at about 102-106C., but are difllcult to purify. The whole amount is thereforemethylated with diazomethane and the methyl-ester obtained afterwardsacetylated with pyridin and acetic anhydride. The methyl-ester (FormulaVI) which has been purified in this way is further purifiedchromatographically, whereby elution of the product required from thealuminium oxide can be effected with petroleum ether, or more quicklywith a mixture of equal parts of benzene and petroleum ether. Theresidues obtained after evaporating down the latter extracts give, onrecrystallization from a mixture of ether and petroleum ether, colorlessplatelets which melt at 135-136 C. A side product can be extracted byafterwards washing the column with a mixture of benzene and ether; itmelts indefinitely at about 162-168 C., but was not furtherinvestigated.

To determine the constitution, a sample of the substance melting at135-136" C. was hydrogenated with platinum oxide in acetic acid, thusgiving acetyl-nor-lithocholic-acid-methyl-ester (Formula VIII, M. Pt.161-162 C., which proved to be identical with a sample prepared bydegradation of lithocholic acid.

The ester (Formula VI) M. Pt. 135-136 C. has a specific rotation [11]+562 =b2 (c= 1.087 in acetone) (e) 1 g. of the acetylated methyl-ester(Formula VI) is dissolved in'2.5 c. c. chloroform and 15 c. c. 1 percent. hydrogen chloride in methyl alcohol and the whole allowed to standfor 16 hours at 20 C. After evaporating down in vacuo, the residue isdissolved in ether, the ether solution washed with dilute hydrochloricacid, soda solution and water, dried over sodium sulphate andconcentrated. By adding petroleum ether A3-hydroxy-nor-cholenic-acid-methyl-ester, Formula VII, M. Pt. 140-142C., is obtained. A sampie is recrystallized from a mixture of ether andpetroleum ether and gives colorless crystals melting at 142-143 C.

(I) For further degradation to the bisnoracid, a Grlgnard solution isprepared from 0.85 g. magnesium filings, 3 c. c. brombenzene and 11 c.c. ether. To this mixture a solution of 900 mg. of the dry methyl-ester(Formula VII) in 8 c. c. absolute benzene is added and the mixturetreated as described above. The crude product obtained is again boiledwith alcoholic caustic potash and again worked up until the crudecarbinol, Formula IX, is obtained. The latter did not form crystals.Acetylation with acetic anhydride and pyridine at room temperature (16hours) gives the acetylated crude product, Formula X, which also doesnot crystallize out and is therefore boiled directly with 8 c. c.glacial acetic acid for 2 hours.

On working up. the crude ethylene compound, Formula XI, is obtained. Itcan be purified chromatographically and obtained as an almost colorlessresin.

0.8 g. of this resin is dissolved in 1 c. c. chloroiorm and 3 c. c.glacial acetic acid and allowed to stand for 3 hours at 25-30 C. withthe solution of 500 mg. chromium trioxide in 0.5 c. 0. water and 2.5 c.c. glacial acetic acid. The mixture is then separated into neutral andacid components. The latter are allowed to stand for 30 minutes with asolution of diazomethane in ether and the methylester obtained isacetylated with 0.6 c. c. absolute pyridine and 0.4 c. c. aceticanhydride for 16 hour at room temperature. On working up, the crudeester shown in Formula XIII is obtained, which is purified bychromatography and, on recrystallization from petroleum ether, formscolorless prisms melting at 101-102 C. Specific rotation (g)Saponification of the acetylated methylester, Formula XIII, with a. 1per cent. solution of hydrogen chloride in methyl alcohol (see above)ves the free A -ii-hydroxy-bisnor-cholenicacid-methyl-ester, FormulaXIV, which crystallizes in fine needles from a mixture 01' ether andpetroleum ether and melts at 109-110 C.

(71.) The hydroxy-ester, Formula XIV, is caused to react in a similarway as described under a, b and c with phenyl-magnesium bromide (FormulaXV) is acetylated (Formula XVI) and thoroughly boiled with glacialacetic acid (Formula XVII) and then is oxidizedaccording to dwith excesschromic acid at about 25 C. A =-3-acetoxyetiocholenic-acid, FormulaXVIlI, is obtained. Reaction with diazomethane gives the correspondingmethyl-ester (Formula XIX) 'which crystallizes from petroleum ether inneedles, melts in the pure form at 99-100 C. and has the specificrotation The A -3-hydroxy etiocholenic-ac-id-methylester, Formula XX,obtained from the latter with a 1 per cent. solution of hydrogenchloride in methyl alcohol, melts at 124-126 C. and has a specificrotation [a]3= +77.7i2(c=0.875 in acetone) C CH:

Grignard reagent HaC OOCH:

(II) 1 Acetylstion Colin Cm (IV) I Oxidation Elimin atinn (In) 1 waterMethylation and acetylation H CH:

H20 17000118 CH3CO0" \J (VI) l Hydmganntion m CH:

, m p im,

(VII') l Grlmudmzon! 5 HaC OH (IX) R= HaC l (XI) 1 Oxidation c0011 HCQHlCOO" (X11) 1 Methylation 5 CH: CH:

a l m 1z=m B=CHaO0) Elimination 1. 01 water aas'moe cm om 1\ CIHIInstead oi by acetylation the intermediate protection of the S-hydroxylgroup may be eiIected by conversion into any other derivative of thehydroxyl which upon hydrolysis can be reconverted into hydroxyl, e. g.any ester or ether group. Instead oi by passing over the diphenylcarbinols the degradation may be effected by introducing any otherhydrocarbon radical, so that for example the dimethyi, diethyl,dipropyl, dicyciohexyl carbinols and ethylenes are obtained. Thetertiary carbinols and the corresponding ethylene compounds areequivalent ior the oxidation step so that instead of the ethylenecompoundsas described in this exampie--also the tertiary carbinols maybe oxidized, e. g. with chromic acid.

Ii one starts irom the A= -3-hydroxy-cholenicacid-methyl-ester insteadoi irom the A -isomer, the corresponding degradation products,containing a double bond in 9:11-position are obtained.

Instead oi the Wieland method described there may be used the Curtius orHoimann method ior this gradual degradation or the side chain may bedegraded by radical oxidation.

What I claim is:

1. In a process for the manuiacture oi compounds of thecyclopentanopolyhydrophenanthrene series, the step oi subjecting amember selected irom the class consisting of a compound oi the series oicholanic acid, its lower homologues and the stereoisomers thereof, beingsubstituted in ring A and containing a double bond in one oi thepositions 9:11 and 11:12, to oxidation by treating the same with chromicacid, whereby degradation oi the side chain is eiiected.

2. Process ior the manuiacture oi compounds oi thecyclopentanopolyhydrophenanthrene series, comprising subiectinl a memberselected irom the class consisting oi a compound oi the series oicholanic acid, its lower homologues and the stereoisomers thereoi, beingsubstituted in ring A and containing a double bond in one oi thepositions 9:11 and 11:12, to degradation oi the side chain according tothe Wieland process by reacting the same with an organo-metalliccompound to produce the corresponding tertiary carbinol, and thenoxidizing the product by treating the same with chromic acid, wherebythe side chain degradation is eiiected.

3. Process for the manufacture oi compounds oi thecyclopentanopolyhydrophenanthrene series, comprising subjecting a memberselected from the class consisting of a compound oi the series oicholanic acid, its lower homologues and the stereoisomers thereof, beingsubstituted in ring A and containing a double bond in one 01' thepositions 9:11 and 11:12, to degradation oi the side chain according tothe Wieland process by reacting the same with an organo-metalliccompound to produce the corresponding tertiary carbinol, dehydrating thecarbinol by treating the same with acetic anhydride, and oxidizing theresultant ethylene compound by treating the same with chromic acid,whereby the side chain degradation is effected.

4. Process for the manufacture of compounds oi thecyclopentanopolyhydrophenanthrene series, comprising subjecting a memberselected irom the class consisting of a compound or the series ofcholanic acid, its lower homologues and the stereoisomers thereoi, beingsubstituted in ring A and containing a double bond in one of thepositions 9:11 and 11:12, to a radical degradation of the side chain bytreating the same with chromic acid with intermediate protection oihydroxyl groups and carbon double bonds.

5. A compound of the 10,13-dimethyl-cyclopentanopolyhydrophenanthreneseries containing a double bond in one of the positions 9:11 and 11:12and, in i'l-position, the substituent wherein n stands ior a wholenumber from 0 to 2, and R stands ior a hydrocarbon radical], and alsocontaining in the 3-position a member selected irom the group consistingof hydroxyl and a radical which upon hydrolysis is converted intohydroxyl.

7. A -3-acetoxy-etiocholenic acid.

TADEUS REICHIS'I'EIN.

